Posterior reversible encephalopathy syndrome in SARS‐CoV‐2 infection: A case report and review of literature

Abstract Consider PRES in SARS‐CoV‐2 infected patients who develop encephalopathy, seizures or impaired vision; especially if the disease is complicated by respiratory distress and need for mechanical ventilation.

tonic-clonic seizure while she was asleep. She had developed fever, myalgia, and dry cough 2 days earlier which she did not seek medical care for. Her past medical history was relevant for aplastic anemia diagnosed 3 years ago and treated with cyclosporine 100 mg/day, danazol, and folic acid. She was waiting for a bone marrow transplantation scheduled on July 2020.
On physical examination, she was febrile (T:39°C) with blood pressure of 130/80 mmHg, heart rate of 100 bpm, respiratory rate of 21/min with oxygen saturation of 89% in room air, and no signs of meningeal irritation. She was lethargic with normal-sized and reactive pupils, no focal neurologic deficit, and downward plantar reflexes. She was transferred to the intensive care units (ICU) and received levetiracetam to control seizures.
Nasopharyngeal real time polymerase chain reaction (RT-PCR) was positive for SARS-CoV-2 infection. Brain CT scan showed hypodensities in posterior regions and brain magnetic resonance imaging (MRI) also displayed subcortical white matter T2/fluid-attenuated inversion recovery (FLAIR) hypersignalities in bilateral parietooccipital regions extending to bifrontal areas, suggestive of PRES ( Figure 2). Cyclosporine was discontinued. She was started on steroids (dexamethasone 8 mg three times a day) and meropenem to treat potential concomitant bacterial infection. Treatment with Hydroxychloroquine was not initiated due to a case of PRES associated with its use.
The day after, her respiratory distress worsened and she was placed on invasive mechanical ventilation. Concerning her immunocompromised condition, serologic evaluation for other opportunistic infections including cytomegalovirus (CMV), Toxoplasma, herpes simplex virus, and Epstein-Barr virus was requested and turned negative for acute infection. Cerebrospinal fluid (CSF) evaluation was not done due to thrombocytopenia. Seizures did not recur but after a week she unfortunately passed away due to severe respiratory distress syndrome and cardiac arrest. A brain autopsy was denied by her family.

| DISCUSSION AND CONCLUSIONS
We presented a 44-year-old White female with a known history of aplastic anemia who presented with severe SARS-CoV-2 infection and CNS involvement in the form of PRES. PRES is a reversible subcortical vasogenic brain edema mostly in the bilateral parieto-occipital regions, caused by disruption of vascular autoregulation or direct effects of cytokines on the endothelium which results in endothelial dysfunction and breakdown of the blood-brain-barrier. 5 It has been described in the setting of eclampsia, renal failure, extreme blood pressure instabilities, cytotoxic or immunosuppressive medications, autoimmune disorders, sepsis, and many other potential causes. 6 Our patient had a history of aplastic anemia and was receiving cyclosporine. Cyclosporine is a well-established cytotoxic medication in the etiologic list of PRES 7-9 ; however, she was clinically stable on cyclosporine for over 3 years. It seems that SARS-CoV-2 infection might have pulled the trigger for the development of PRES in this patient. Also it is reported that there is a link between patients suffering from PRES and showing pancytopenia in the lab results. 10 In a thorough search of the literature and after excluding articles focusing on brain imaging findings and lacking necessary clinical data, we found 18 articles reporting 24 patients with PRES in the setting of SARS-CoV-2 infection. Patients' characteristics (including our patient) are presented in Table 1. Subjects were between 25 and 74 years old, with a female predominance (16 women). Seventeen patients (68%) had a preexisting medical condition with hypertension being the most common followed by diabetes mellitus and hyperlipidemia. Two patients were pregnant women at term, and eight had no history of any medical disorders. It has been stated that nearly half of patients with PRES have a history of an autoimmune disorder 5 ; however, this was not the case in any of the patients previously reported except for our patient who had a history of aplastic anemia. This finding indicates that the pattern of developing PRES in SARS-CoV-2 infected patients is different from other population samples.
About 19 patients (76%) had respiratory involvement of which 18 were in need of mechanical ventilation. The course of hospitalization was further complicated in 18 patients, including acute kidney injury in 10 (40%). Interestingly renal failure has been suggested as the strongest predictor for the development of PRES 5 and it has been reported in 55% of patients. Six patients developed liver injury, and four cases were complicated by septic shock. Blood pressure recordings above 140/90 mmHg were reported in 18 (72%) patients. Hypertension and respiratory involvement were the strongest predictors of PRES in SARS-CoV-2 infected patients.
Fourteen patients (56%) received hydroxychloroquine (HCQ) for COVID treatment. PRES associated with HCQ use has previously been reported. 11,12 However; it has exclusively been in the setting of systemic lupus erythematous or other immunologic disorders. Whether HCQ plays a role in developing PRES needs further studies. Seven patients (28%) received immune therapies including Anakinra and Tocilizumab. PRES symptoms were detected as early as the first day of SARS-CoV-2 presentation until the 6th week throughout admission. The course of PRES was favorable with improvement in 80% of patients.
It is believed that hypoxic ischemic damage to the endothelial cells, excessive cytokines release, immune thrombotic microangiopathy, and direct viral induced endothelial cell injury are accountable for endothelial dysfunction and the resulting cerebral edema and PRES in patients with severe SARS-CoV-2 infection. In the setting of an acute inflammatory response, lymphocytes and monocytes produce large amounts of circulating cytokines including tumor necrosis factor α, interleukin 1, and interferon γ, which in turn result in endothelial dysfunction and blood brain barrier breakdown. 5 Although our patient did not respond to steroid therapy, based on above theories, steroids seem reasonable in the setting of SARS-CoV-2-induced PRES and there is actually one report of good response to them. 13 It is also worthy to mention that a pattern of complement-mediated microvascular injury and procoagulant state have been described in the lungs and/or skin of five patients with severe SARS-CoV-2 infection. 14 We presented a patient with a history of aplastic anemia who presented with symptoms of PRES a few days after SARS-CoV-2 infection. We also reviewed other reported cases of PRES in the setting of SARS-CoV-2 infection. We suggest physicians to consider PRES in SARS-CoV-2 infected patients who develop encephalopathy, seizures, or impaired vision; especially if the disease is complicated by respiratory distress and need for mechanical ventilation and labile blood pressure and hypertension. More studies are needed to clarify the mechanism of PRES in SARS-CoV-2 infected patients; meanwhile excessive cytokine release and complement mediated endothelial injury are considered accountable.